Of the estimated 225,000-296,000 people in the United States with a spinal cord injury and/or disorder (SCI&D), more than 25,000 receive care through the VA health care system. Disruption of corticospinal pathways results in impaired muscle activation below the level of the lesion. For individuals with cervical level injuries, the ability to grasp and manipulate objects is lost or diminished, impacting independence and social participation. A recent survey of 347 individuals with tetraplegia identified restoration of hand and arm function as the top priority related to functional recovery. The pathophysiology of chronic SCI may limit or even prevent functional improvement through traditional therapies, fostering the need for new treatments that promote spinal cord regeneration and maximize function through spared neural pathways. Chronic paralysis leads to functional reorganization in the brain, reducing the neural capacity available to immobilized limbs, further challenging recovery of function. Therefore, a key to improving function after SCI is to develop new therapies that directly influence the function of neurons in the brain and spinal cord and engage the mechanisms of neuroplasticity needed to facilitate recovery of function. Neuroplasticity plays a critical role as it enables the nervous system to adapt, strengthening spared corticospinal connections. We aim to develop a novel BCI neurofeedback paradigm that combines the advantages of biofeedback, motor imagery, and action observation and imitation to facilitate motor cortex activation in veterans with tetraplegia. By directly targeting neuronal activity, we aim to facilitate neuroplasticity measured as increased cortical activity amplitude and voluntary control over cortical modulation. In this study we will measure cortical activation using magnetoencephalography (MEG) during observed, imagined, imitated, and overt upper limb movements in veterans with tetraplegia and an unimpaired control group. This baseline evaluation allows us to compare cortical activation during simple movement tasks between individuals with tetraplegia and in a group of able-bodied subjects. We will focus on two movements, one that subjects with tetraplegia cannot perform overtly due to complete paralysis and a second movement limited by partial paralysis. For the movement impaired by complete paralysis, subjects imagine performing the movement along with a video of an experimenter performing the action (action observation). For the movement with residual function, subjects will perform the movement to their best ability along with the visual feedback (action imitation). The video displayed in both training activities, action observation, and imitation, engages the mirror neuron system, which is a potent facilitator of motor cortex excitability. Once we identify the cortical areas responsible for intended movement in subjects with tetraplegia, we will use MEG to provide neurofeedback by coupling the action of a virtual hand display to MEG signal modulation in real-time. Similar to biofeedback, a physiological signal is being used to influence behavior, in this case cortical modulation. By coupling the MEG signals to a virtual hand, we activate the mirror neuron system which will map the observed action onto the subject's own motor representation. We believe that this neurofeedback training paradigm can be used to strengthen corticospinal pathways to the impaired upper limb, thus improving function (increased strength) in muscles with partially intact corticospinal pathways. In combination with BCI technology or spinal cord regeneration, enhancing cortical activation may augment motor control when voluntary control has been lost. PUBLIC HEALTH RELEVANCE: Project Narrative Relevance to Veterans Health. More than 25,000 individuals with spinal cord injuries (SCIs) receive care through the VA health care system. Functional electrical stimulators controlled by cortical activity are being developed to restore upper limb function for people with motor impairments, including those with SCI. Others are working towards spinal cord repair or regeneration techniques. Both of these therapies require intact motor control programs within the brain. We aim to develop a neurofeedback paradigm that influences the function of neurons in the brain and spinal cord thus promoting neuroplasticity and facilitating the recovery of function. Completion of this work will provide a foundation for new rehabilitative strategies for veterans with SCI that will hopefully translate to an improved quality of life.